This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California San Diego in consortium with The Salk and The Burnham Institutes. The major goals of the Center over the next five years will be to expand our efforts into early clinical identification of Alzheimer's disease (AD) and studying mechanisms of neurodegeneration and repair. Projects will focus on semantic memory in AD, potential mechanisms of neurodegeneration in AD, alpha-synuclein biology, and mechanisms whereby hormones or environment may enhance neuronal survival. In addition, we will continue to carry out detailed clinicopathological correlations and studies of the course of AD. This Center will continue to maintain extremely strong Clinical and Neuropathology Cores. The Clinical Core will continue to longitudinally characterize a cohort of approximately 475-500 subjects to study early changes in cognition and semantic memory, and to provide other AD investigators and the San Diego community as a whole with a well- characterize clinical cohort of both Caucasian and Hispanic volunteer who undergo annual evaluations and are willing to participate in clinical research. The Clinical Core will also recruit special subjects and controls to support the special needs of many of the individual projects. Subjects will also participate in multi-center drug trials. Data derived from subjects will be used in collaborative research. We will place increasing emphasis in identifying genetic influence that either accelerate or protect individuals from the development of AD. In addition, we will continue to focus our studies on the 15-20% of individuals with AD who also have Lewy bodies in their cortex and represent the second most common form of dementia in the United States. The Neuropathology ore will continue to refine the diagnosis of AD and LBD, provide diagnoses, clinicopathological correlations, and brain tissue. The Center as a whole will continue to provide brain tissue, fibroblasts, plasma, DNA, and cerebrospinal fluid to investigators upon request. The ADRC provides a setting to facilitate research training of investigators and will transfer information to the profession and lay communities through our mini-residency program, conferences and other educational activities. The Biostatistics Core will continue to modernize the database and will: 1) maintain the database for the Center, 2) transmit data as requested for the Alzheimer's Disease Data Coordinating Center, 3) provide consultations and statistical expertise for projects emanating from the cores, projects and pilots. Our specific research projects in this renewal include: the role of caspase cleavage in neurodegenerative disease (Bredesen), regulation of neurogenesis in the adult mammalian hippocampus (Gage), NACP/alpha-synuclein and the mechanism of neurodegeneration in Lewy body disease (Masliah), cognitive studies of semantic memory in AD (Salmon), and estrogen mediated neuronal plasticity in the brain (Tuszynski). A mechanism is also outlined for the awarding of pilot feasibility studies.